The present invention, in some embodiments thereof, relates to genetically modified muscle cells for the treatment of neurodegenerative disorders.
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, was first described in 1869 by a French neurologist, Jean Martin Charcot. This is a progressive, lethal disease that leads to degeneration of upper and lower motor neurons. Death of the upper motor neurons found in the motor cortex in the brain, leads to spasticity, hyperexcitability of reflexes and the appearance of pathological reflexes. The death of the lower motor neurons, which is found in the brain stem and in the spinal cord, leads to weakness and atrophy of the muscles followed by progressive paralysis.
ALS has a worldwide prevalence of 1-2 per 100,000, and mortality is caused within 3-5 years of the onset of the disease due to respiratory failure. ALS occurs mainly in adults (45-60 of age), and most cases are sporadic, although 5 to 10% of ALS cases are inherited in an autosomal dominant pattern of which about 20% are caused by a mutation in the Cu/Zn superoxide dismutase (SOD1) gene on chromosome 21. The disease results from the over-activity of the SOD1 gene and not from the damage in its antioxidant activity. The etiology of sporadic ALS is unknown, although it is generally believed that sporadic and familial ALS may share pathological mechanisms.
The pathophysiology of the disease includes a reduced secretion of neurotrophic factors (NTFs), protein aggregations, malfunctioning of the mitochondria, rupture in the axonal passage, destruction in the calcium metabolism, changes in the skeletal proteins, high levels of glutamate and oxidative damage. Preventing or slowing motor neurons degeneration and death in ALS are critical goals of future therapies, as are means of enhancing axonal regeneration.
Several studies concerning peripheral nerve pathology have demonstrated that neurotrophic factors play an important role in the development, maintenance and regeneration of the nervous system. The brain derived neurotrophic factor (BDNF) was shown to prevent the loss of motor units and to contribute to the maintenance of muscle mass when administered to the hind limb muscles of mice after peripheral nerve injury. The glial derived neurotrophic factor (GDNF) and the insulin growth factor 1 (IGF-1) are two of the most potent survival factors known for peripheral neurons. Several studies have shown that both GDNF and IGF-1 can prevent neuronal degeneration in mice and rats after axotomy, as well as the programmed cell death of motor neurons during development [3, 6-9]. In the SOD1G93A transgenic mice model for amyotrophic lateral sclerosis (ALS), overexpression of GDNF and/or IGF-1 in muscles, resulted in hyperinnervation of the muscles by motor neurons [3, 6-13]. Moreover, GDNF is important for neuron branching at the NMJ and for modulating synaptic plasticity [14]. Increased expression of GDNF in the muscles of SOD1G93A transgenic mice delays disease onset, improves locomotor performance, and increases their lifespan. In addition, the survival of motor neurons is increased when GDNF levels in the muscles of SOD1G93A transgenic mice are high. The vascular endothelial growth factor (VEGF) is another factor contributing to the pathogenesis of ALS and the increased expression of VEGF in motor neuron of SOD1G93A transgenic mice, augmented their survival and enhanced motor performance [15-16]. Moreover, intracerebroventricular administration of VEGF in a rat model of ALS, dramatically increased motor neuron survival and an intraperitoneal injection of VEGF led to the preservation of NMJs [17-18]. Unfortunately, clinical trials of systemic or intrathecal administration of growth factors to ALS patients have not been effective, probably due in part to their short half-life, low concentrations at target sites, and high incidence of side effects [10-11].
Sarig et al., [Stem Cells 2006; 24: 1769-1778] teaches isolated populations of muscle progenitor cells (MPCs).
Mohajeri et al [Human Gene Therapy, 10:1853-1866 (Jul. 20, 1999) teaches the use of primary myoblast cells genetically modified to express GDNF for the treatment of motor neuron diseases.
U.S. Patent Application No. 20050238625 teaches the use of skeletal muscle cells genetically modified to express neurotrophic factors for the treatment of nerve diseases.
U.S. Patent Application No. 20030161814 teaches the use of skeletal muscle cells genetically modified to express GDNF for the treatment of motor neuron diseases.